Open AccessAn autocrine ActivinB mechanism drives TGF β/Activin signaling in Group 3 medulloblastoma
Author(s) -
Morabito Morgane,
Larcher Magalie,
Cavalli Florence MG,
Foray Chloé,
Forget Antoine,
MirabalOrtega Liliana,
Andrianteranagna Mamy,
Druillennec Sabine,
Garancher Alexandra,
MasliahPlanchon Julien,
Leboucher Sophie,
Debalkew Abel,
Raso Alessandro,
Delattre Olivier,
Puget Stéphanie,
Doz François,
Taylor Michael D,
Ayrault Olivier,
Bourdeaut Franck,
Eychène Alain,
Pouponnot Celio
Publication year - 2019
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201809830
Subject(s) - autocrine signalling , medulloblastoma , transforming growth factor , mechanism (biology) , signal transduction , microbiology and biotechnology , activin type 2 receptors , tgf beta signaling pathway , cancer research , medicine , biology , receptor , physics , quantum mechanics
Medulloblastoma ( MB ) is a pediatric tumor of the cerebellum divided into four groups. Group 3 is of bad prognosis and remains poorly characterized. While the current treatment involving surgery, radiotherapy, and chemotherapy often fails, no alternative therapy is yet available. Few recurrent genomic alterations that can be therapeutically targeted have been identified. Amplifications of receptors of the TGF β/Activin pathway occur at very low frequency in Group 3 MB . However, neither their functional relevance nor activation of the downstream signaling pathway has been studied. We showed that this pathway is activated in Group 3 MB with some samples showing a very strong activation. Beside genetic alterations, we demonstrated that an ActivinB autocrine stimulation is responsible for pathway activation in a subset of Group 3 MB characterized by high PMEPA 1 levels. Importantly, Galunisertib, a kinase inhibitor of the cognate receptors currently tested in clinical trials for Glioblastoma patients, showed efficacy on orthotopically grafted MB ‐ PDX . Our data demonstrate that the TGF β/Activin pathway is active in a subset of Group 3 MB and can be therapeutically targeted.